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Receptor protein found to be a key player in prostate cancer cells’ drug resistance

Researchers have identified a receptor protein often known as CHRM1 as a key player in prostate cancer cells’ resistance to docetaxel, a commonly used chemotherapy drug to treat advanced cancer that has spread beyond the prostate. The invention opens the door to recent treatment strategies that would overcome this resistance. This might ultimately help extend the lives of those with prostate cancer, one in every of the leading causes of cancer deaths amongst men.



Led by a team of scientists at Washington State University, the study showed that blocking CHRM1 in resistant prostate cancer cell lines and an animal model based on patient-derived resistant tissue restored docetaxel’s ability to kill cells and stop tumor growth. The researchers did this through the use of dicyclomine, a drug that selectively inhibits CHRM1 activity. Dicyclomine is already in the marketplace as a generic drug and is currently used to treat symptoms of irritable bowel syndrome.

The effect was pretty dramatic in all of the experimental models we tested. And since dicyclomine already has a clinical use, this work has immediate translational potential.”

Boyang (Jason) Wu, associate professor within the WSU College of Pharmacy and Pharmaceutical Sciences and co-senior writer on the study

Published within the journal Cell Reports Medicine, the researchers’ findings support clinical testing to substantiate whether combined use of docetaxel and dicyclomine could help overcome treatment resistance in prostate cancer patients. Docetaxel resistance can develop in prostate cancer after about six months of treatment. Chemotherapy drugs like docetaxel are amongst only a few options available to patients with castration-resistant prostate cancer, a lethal type of the disease that not responds to hormone therapy.

Wu said this sort of combination therapy could also potentially be used for other cancers which are currently being treated with docetaxel, corresponding to breast and lung cancer. It may be possible to make use of the identical combination strategy with other similar chemotherapy drugs.

Along with testing resistant cancer cell lines, the research team also tested cells that also responded to docetaxel treatment. They found that using dicyclomine to dam CHRM1 in these cells made docetaxel more efficient at killing them. Wu said that this shows that prostate cancer patients could potentially profit from a mix treatment strategy even before docetaxel resistance develops.

“What this means is that the bottom effective dose of docetaxel could also be lower when the drug is combined with dicyclomine, in comparison with when docetaxel is used alone,” Wu said. “Having the ability to use a lower dose could help reduce unwanted unwanted side effects and make treatment more manageable for patients.”

Other than Wu, co-authors on the study include co-senior writer Tyler Bland-;a former WSU postdoctoral fellow who’s now a clinical assistant professor on the University of Idaho-;in addition to co-first authors Jing Wang, a recent WSU PhD graduate, and Jing Wei, a WSU postdoctoral fellow. The research team conducted the study in collaboration with scientists on the University of Washington, Medical University of Innsbruck in Austria and National Yang Ming Chiao Tung University in Taiwan.

Funding for this study got here from a U.S. Department of Defense Prostate Cancer Research Program grant with additional support provided by the National Cancer Institute, a component of the National Institutes of Health, and WSU College of Pharmacy and Pharmaceutical Sciences startup funds.

Source:

Journal reference:

Wang, J., et al. (2024) Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer. Cell Reports Medicine. doi.org/10.1016/j.xcrm.2023.101388.

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